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![Epidermal and Epidermal-
Dermal Cohesion
• The hemidesmosomal components comprise:
1. Cytoplasmic proteins [ plakin homologues (plectine,
BPAG1)]
2. Trasmembrane components [integrins, and collagenous
transmembrane (BPAG2)].
• All basement membranes contain collagen IV, laminins,
nidogens, and perlecan.
• Anchoring fibrils ( to the dermis) are composed mainly of
collagen VII](https://image.slidesharecdn.com/bullouslesions-230212155330-1591c28a/75/Bullous-lesions-pdf-9-2048.jpg)
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Bullous lesions.pdf
- 1. Bullous dermatoses Dr HalaAbi-Rached Megarbane Associate Professor University of Balamand
- 2. Classification • Acquired: (autoimmune, infectious,toxiderma) • Hereditary: (Epidermolysis Bullosa, ichtyosis bullosa ) Fine JD, Management of acquired bullous skin diseases; New England Journal of Medecine. Bickle K, Roark T; Autoimmune Bullous dermatoses: A Review; American family physician.
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- 6. Epidermal and Epidermal-Dermal Cohesion •Desmosomes, hemidesmosomes, and the epidermal basement membrane • They represent distinct molecular adhesion complexes • Mutations in the genes encoding protein components of the above cause hereditary skin diseases • These proteins are targeted in autoimmune skin blistering diseases ( pemphigus or pemphigoid group and in epidermolysis bullosa acquisita)
- 7. Epidermal and Epidermal-Dermal Cohesion •The major components of desmosomes belong to three major gene families: Plakins (desmoplakins) , Armadillo proteins (plakophilins and plakoglobins), and Desmosomal cadherins (desmogleins, desmocollins). Cytoplasmic proteins (desmoplakins , plakophilins and plakoglobins) and Transmenbrane proteins (desmogleins and desmocollins)
- 9. Epidermal and Epidermal- DermalCohesion • The hemidesmosomal components comprise: 1. Cytoplasmic proteins [ plakin homologues (plectine, BPAG1)] 2. Trasmembrane components [integrins, and collagenous transmembrane (BPAG2)]. • All basement membranes contain collagen IV, laminins, nidogens, and perlecan. • Anchoring fibrils ( to the dermis) are composed mainly of collagen VII
- 14. Autoimmune Bullous Dermatoses •Pemphigus vulgaris • Paraneoplastic pemphigus • Bullous pemphigoid • Herpes gestationis • Cicatricial pemphigoid • Dermatitis herpetiform • Linear IgA dermatosis • Epidermolysis bullosa acquisita
- 15. Pemphigus vulgaris • Meanage of onset: 40-60 years • Skin and mucous membranes • Fatal if not treated
- 16. Pemphigus vulgaris • Lesionsstart in the oral mucosa • Followed by skin lesions • Flaccid blisters, fragile, rupture easily, painful erosions. • Site of predilection (scalp, face, chest, axillae, groin, umbilicus, pharynx, larynx, oral cavity)
- 17. Painful erosions inthe oral cavity
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- 20. Pemphigus Vulgaris • Light:Suprabasilar blister with acantholysis • DIF: Intercellular IgG and C3 • IIF: Circulating antibodies against keratinocytes membranes • Target antigen: Desmoglein 3 (130 Kd), localised in desmosomes.
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- 24. Treatment • Oral corticosteroids(1mg/kg/day) + immunosuppressive agents. • Azathioprine, Mycophenolate Mofetil, Methotrexate, Cyclophosphamide • Plasmapheresis
- 25. Paraneoplastic Pemphigus • Mostcommon malignancy associated is non-Hodgkin lymphoma • Next most common in frequency are chronic lymphocytic leukemia, Castleman’s disease, and thymoma. • Also: Waldenstrom’s macroglobulinemia, sarcomas
- 26. Paraneoplastic Pemphigus Clinical findings •The signature clinical finding is the early onset of severe refractory oral mucosal involvement.
- 28. Paraneoplastic Pemphigus - Histology • Suprabasilaracantholysis and basal cell vacuolation + lymphocytic exocytosis and dyskeratotic keratinocytes • IgG + C3 deposits within the intercellular spaces and along the basement membrane • Desmoplakin I and II
- 30. Paraneoplastic Pemphigus Evolution andtreatment May precede clinical appearance of neoplasm • Very poor prognosis • Treatment usually unsuccessful • Remission if a benign tumor is resected • Immunosuppressive treatment, plasmapheresis, immunophoresis.
- 31. Autoimmune Bullous Dermatoses •Pemphigus vulgaris • Paraneoplastic pemphigus • Bullous pemphigoid • Herpes gestationis • Cicatricial pemphigoid • Dermatitis herpetiform • Linear IgA dermatosis • Epidermolysis bullosa acquisita
- 32. Bullous Pemphigoid • Mainlyin the elderly, rarely in children • Involvement of mucous membranes <<< PV • May start as urticarial eruption, pruritus+++ • Blisters are tense, less easily ruptured • Topography: medial thighs, axillae, groin, abdomen, flexor forearms, lower legs, oral cavity, anus, genital mucosa. • No scar formation following the lesions of PB.
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- 34. Bullous Pemphigoid • Subepidermalblister, dermal inflammation ( L, H, Eo) • EM: Lamina lucida of BM ( loss of anchoring filaments and hemidesmosomes) • DIF: deposition of IgG and C3 along the basement membrane in a linear pattern • IIF: IgG antibodies against basement membrane zone • Target antigen: Pemphigoid antigen 1 (230 KD ) and 2 ( 180 KD) localised in hemidesmosomes
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- 38. Treatment • Systemic corticosteroids( 0.5 to 1mg/kg/day) • + Immunosuppressive agents ( Azathioprine :100 to 150 mg/day or Mycophenolate Mofetil: 2 g/day or Methotrexate: low-dose methotrexate as a steroid-sparing agent) • Anti-TNF • Very potent topical corticosteroids in localised cases
- 39. Autoimmune Bullous Dermatoses •Pemphigus vulgaris • Paraneoplastic pemphigus • Bullous pemphigoid • Herpes gestationis (Pemphigoid Gestationis) • Cicatricial pemphigoid • Dermatitis herpetiform • Linear IgA dermatosis • Epidermolysis bullosa acquisita
- 40. Herpes gestationis or Pemphigoid Gestationis •Bullous pemphigoid of pregnancy • Develop during the second and third trimesters • Abrupt onset of extremely pruritic urticarial papules and blisters (abdomen,trunk) • Resolves spontaneously within weeks to months after delivery • Dramatic flares can occur at or immediately after delivery • May recur with subsequent pregnancies
- 44. Herpes Gestationis • Noincrease in fetal or maternal mortality • Greater prevalence of premature and small-for-gestational-age (SGA) babies • 5-10% of infants born to affected mothers may present with transient cutaneous involvement that resolves as maternal autoantibodies are cleared.
- 45. Treatment • Prednisone at0.5 mg/kg/d (starting dose) • Tapered to minimum dose required to control the disease • Steroid-sparing agents may be used after delivery in resistant cases • Topical steroids may be initiated in mild cases
- 46. Autoimmune Bullous Dermatoses •Pemphigus vulgaris • Paraneoplastic pemphigus • Bullous pemphigoid • Herpes gestationis • Cicatricial pemphigoid • Dermatitis herpetiform • Linear IgA dermatosis • Epidermolysis bullosa acquisita
- 47. Cicatricial Pemphigoid • Severeerosive lesions of the skin and mucous membrane • Skin involvement in 1/3 of patients • Tense bullae, erosions, ulcers • Healing with scars • Ocular lesions scarring, fibrosis, blindness • Esophagus occlusion, supraglottic stenosis
- 49. Cicatricial Pemphigoid • Subepidermalblisters + mixed inflammatory infiltrate • Fibroblast proliferation in older lesions • DIF: linear deposition of C3 and IgG along the basement membrane ( IgA and IgM ) • EM: loss of anchoring filaments • Target Antigens: BPA2 (180 KD), laminin-5 Ag
- 51. Course and Treatment •Chronic progressive disease • Multidisciplinary approach (otolaryngology, ophtalmology, gastroenterology, gynecology) • Topical corticosteroids ( mouthwash) • Dapsone ( 50 to 100 mg/day) +/- systemic steroids • Ocular involvement: systemic steroids + cyclophosphamide ( 0.5 to 2 mg/kg/j) or azathioprine or mycophenolate mofetil ( 1.5 to 3 g/day) •
- 52. Autoimmune Bullous Dermatoses •Pemphigus vulgaris • Paraneoplastic pemphigus • Bullous pemphigoid • Herpes gestationis • Cicatricial pemphigoid • Dermatitis herpetiform • Linear IgA dermatosis • Epidermolysis bullosa acquisita
- 53. Dermatitis herpetiformis • Onset:20 and 40 years • Papulovesicular and urticarial lesions (wheals) • Extensor surfaces in a symmetric distribution • Pruritus+++ • Associated with a gluten-sensitive enteropathy
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- 56. Dermatitis herpetiformis • Subepidermalvesicles, neutrophilic microabcesses in dermal papillae and dermal infiltration of N + Eo • DIF: IgA in tips of dermal papillae • Positive Antiendomysial, antigliadine, antitransglutaminase antibodies in sera
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- 59. Treatment • Dapsone (2mg/kg/j) or sulfapyridine (= salazopyrine 3 to 6g/j ) • Check G6PD before starting Dapsone • Blood count / month ( hemolytic anemia) • Gluten free diet
- 60. Autoimmune Bullous Dermatoses •Pemphigus vulgaris • Paraneoplastic pemphigus • Bullous pemphigoid • Herpes gestationis • Cicatricial pemphigoid • Dermatitis herpetiform • Linear IgA dermatosis • Epidermolysis bullosa acquisita
- 61. Linear IgA dermatosis •Children and young adults • Pruritic annular papules, vesicules (« collarettes ») • Extensor surfaces, symmetric distribution • Possible mucous involvement
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- 63. Histopathology • Subepidermal bullae •Neutrophils collections (basement membrane, dermal papillary tips) • DIF: linear IgA along basement membrane. • Target Antigen: Basement Membrane Ag (97 kd)
- 64. Treatment • Dapsone (100mg/day) or sulfapyridine ( 1.5 to 3 g/day) • Low-dose prednisone may be required in resistant cases
- 65. Autoimmune Bullous Dermatoses •Pemphigus vulgaris • Paraneoplastic pemphigus • Bullous pemphigoid • Herpes gestationis • Cicatricial pemphigoid • Dermatitis herpetiform • Linear IgA dermatosis • Epidermolysis bullosa acquisita
- 66. Epidermolysis bullosa acquisita •Blistering subepidermal • Skin and mucus membranes • Clinically: blisters, scars, and milia • Trauma-prone areas (extensor surfaces of elbows, knees, ankles, and buttocks) . • Generalized inflammatory skin blister phenotype mimic bullous pemphigoid
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- 68. Patient with epidermolysisbullosa acquisita who has severe blistering, erosions, scarring, and milia formation on trauma-prone areas of her skin. This is the classic presentation
- 69. Histopathology • Subepidermal (belowlamina densa) • DIF: IgG and/or C3 linearly along the dermoepidermal junction • A positive DIF and IgG deposits within the sub- lamina densa zone are necessary criteria for the diagnosis of EBA. • Target antigen : type VII collagen (290 and 145 kd)
- 72. Epidermolysis bullosa acquisita •Related features may include an underlying systemic disease such as inflammatory bowel disease. • Treatment options limited and often difficult
- 73. Classification • Acquired: (autoimmune, infectious,toxiderma ) • Hereditary: (Epidermolysis Bullosa, ichtyosis bullosa ) Fine JD, Management of acquired bullous skin diseases; New England Journal of Medecine. Bickle K, Roark T; Autoimmune Bullous dermatoses: A Review; American family physician.
- 74. Bullous Toxidermic reactions •Erythema multiforme • Stevens-Johnson Syndrome • Toxic epidermal necrolysis
- 75. Erythema Multiforme • Cell-mediatedhypersensitivity reaction • Minor form • Causes: - infectious ( Herpes simplex, Mycoplasma Pneumoniae, Chlamydiae) - drugs • 20% occur in childhood
- 76. Erythema Multiforme • Lesionsare red papules that evolve into target lesions • Blister or crust in the central zone • Topography: face and acral • Mucous membrane involvement: light to severe
- 77. Treatment • Oral corticosteroids?,thalidomide, dapsone, other immunosuppressive agents • Acyclovir, Valacyclovir ( therapeutic trial even if no preceding herpes simplex infection has been documented) • Oral erythromycine (chlamidiae, mycoplasma) • Ophtalmologic care (artificial tears, topical vitamin A)
- 78. Clinical criteria forStevens- Johnson syndrome • Acute mucocutaneous syndrome • Prodrome of upper respiratory illness with fever, cough, headache and malaise • Abrupt onset of symmetrical red papules • Rapid evolution to target lesions, large bullae or extensive areas of denuded skin. • At least two mucosal surfaces involved with erosions and crusting • Duration of at least 3 weeks
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- 82. Eetiology and pathogenesis •Preceding infections with Mycoplasma pneumoniae • Drugs: NSAIDs, anticonvulsivants, penicillins, tetracycline, doxycycline, sulphonaides • Combination of infection and drug
- 83. Pathology • Extensive epithelialnecrosis • Inflamatory infiltrate
- 84. Prognosis and treatment •4 to 6 weeks course • Complications: dehydration, electrolyte imbalance, secondary bacterial infection, cutaneous scarring and dyspigmentation. • Ocular sequalae, contracture over joints
- 85. Prognosis and treatment •Hospitalization • Immediate withdrawal of any suspected drug • Correction of fluid and electrolyte imbalance • Warming the environment • Prevention of secondary infection and sepsis
- 86. Treatment • Use ofcorticosteroids is controversial • May lower the period of acute eruption and fever • May adversely affect morbidity and mortality • Other: Mycophenolate Mofetil, IVIG
- 87. Toxic Epidermal Necrolysis •Severe, life-threatening, bullous disease • Widespread detachment of the epidermis denudation of large areas of body surface > 30% • Mucous membrane +++ • Cause: systemically administered medication • Differential diagnosis: staphylococcal scalded skin syndrome
- 89. Histology • Necrosis ofthe full thickness of the epidermis
- 90. Treatment • Use ofcorticosteroids is controversial and cannot be recommended • IVIG may be of benefit (risk for anaphylaxis) • Supportive treatment +++ (meticulous nursing care in burn units, large volumes of fluids, electrolytes etc…)
- 91. Classification • Acquired: (autoimmune, infectious,toxiderma ) • Hereditary: (Epidermolysis Bullosa, ichtyosis bullosa ) Fine JD, Management of acquired bullous skin diseases; New England Journal of Medecine. Bickle K, Roark T; Autoimmune Bullous dermatoses: A Review; American family physician.
- 92. Epidermolysis Bullosa 3 categories: •EB simplex (EBS) • Junctional EB (JEB) • Dystrophic EB (DEB)
- 94. Epidermolysis Bullosa • Severalsubtypes within each category • Clinically and genetically distinct • Mutations in at least 10 different genes
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- 99. Epidermolysis Bullosa Simplex • Weber-CockayneEBS KRT5 and 14 • Kobner EBS KRT5 and 14 • Dowling-Meara EBS KRT5 and 14
- 102. Epidermolysis Bullosa Simplex • Blisterson hands and feet +++, trunk and limbs • Plamo-plantar hyperkeratosis • Nail dystrophy • Oropharyngeal blistering ( D-M EBS) • Hot environment,friction and trauma may induce blistering
- 104. Epidermolysis Bullosa Simplex • Prognosisis good • Disability, limitations on the distance they can walk…
- 105. Dystrophic Epidermolysis Bullosa • Blisteringbelow the lamina densa • Type VII collagen defect • Tendency of the blisters to heal with mutilating scarring
- 108. Dystrophic Epidermolysis Bullosa • DominantDEB • Generalized Hallopeau-Siemens DEB • Generalized non-Hallopeau-Siemens DEB • Clinical Overlap
- 109. Dystrophic Epidermolysis Bullosa • Tendencyfor blistered area to heal with atrophic scarring • Milia in recently healed areas • Development of joint contractures and fusion of fingers and toes • Tendency for epitheliomas in reccurently ulcerated and scarred areas
- 111. Dystrophic Epidermolysis Bullosa • Blisteringof the oral, pharyngeal and oesophageal mucosa Leading to: - Reduced nutritional intake - Progressive contraction of the mouth - Progressive fixation of the tongue - Oesophageal stricture • Conjunctival bullae • Genitourinary tract strictures
- 112. Prognosis in DEB •Extraordinary variation in prognosis • Correlates with the amount of collagen VII at the basement membrane • Complete absence suggests a worse outlook
- 113. Junctional epidermolysis bullosa •Herlitz JEB laminine 5 • non-Herlitz JEBcollagen XVII laminine 5 • JEB with pyloric atresia integrin alpha6 B4
- 116. Junctional epidermolysis bullosa •EB letalis • Some may survive • Non-cutaneous features +++ cause significant morbidity
- 117. Junctional epidermolysis bullosa - Non-cutaneousfeatures • Integrin ( A6, B4) is found in other epithelia than skin including gastrointestinal and urogenital tract.
- 118. Junctional epidermolysis bullosa •Laryngeal involvement ( hoarseness) • Pyloric atresia • Urogenital tract involvement ( bladder, urethra) • Teeth, eyes
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- 120. Treatment of EB •General skin care ( special non-adhesive dressings and bandages) • Pain control ++++ • Management of complications • Conservative approach ++++
- 121. Classification • Acquired: (autoimmune, infectious,toxiderma ) • Hereditary: (Epidermolysis Bullosa, ichtyosis bullosa ) Fine JD, Management of acquired bullous skin diseases; New England Journal of Medecine. Bickle K, Roark T; Autoimmune Bullous dermatoses: A Review; American family physician.
- 122. Ichtyosis bullosa • Geneticskin disease ( genes encoding keratin) • Widespread blistering in infancy • Blistering improves with age • Hyperkeratosis, desquamation, erythroderma, lichenification…
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